REVIEW URRENT C OPINION

The gut microbiota and inflammatory bowel disease Yoshiyuki Goto a,b, Yosuke Kurashima c, and Hiroshi Kiyono a,c

Purpose of review Inflammatory bowel diseases (IBDs) reflect the cooperative influence of numerous host and environmental factors, including those of elements of the intestinal immune system, the gut microbiota, and dietary habits. This review focuses on features of the gut microbiota and mucosal immune system that are important in the development and control of IBDs. Recent findings Gut innate-type immune cells, including dendritic cells, innate lymphoid cells, and mast cells, educate acquired-type immune cells and intestinal epithelial cells to achieve a symbiotic relationship with commensal bacteria. However, perturbation of the number or type of commensal microorganisms and endogenous genetic polymorphisms that affect immune responses and epithelial barrier system can ultimately lead to IBDs. Providing beneficial bacteria or fecal microbiota transplants helps to reestablish the intestinal environment, maintain its homeostasis, and ameliorate IBDs. Summary The gut immune system participates in a symbiotic milieu that includes cohabiting commensal bacteria. However, dysbiotic conditions and aberrations in the epithelial barrier and gut immune system can disrupt the mutualistic relationship between the host and gut microbiota, leading to IBDs. Progress in our molecular and cellular understanding of this relationship has yielded numerous insights regarding clinical applications for the treatment of IBDs. Keywords commensal microbiota, dysbiosis, fecal microbiota transplantation, innate lymphoid cells, mast cells

INTRODUCTION The intestinal tract is constitutively exposed to countless antigens, including dietary materials and commensal and pathogenic microorganisms. To deal with this barrage, the finely tuned host immune system discriminates between favorable and unfavorable antigens at mucosal sites; this mucosal immune system concurrently induces and regulates reciprocal responses that lead to antigenic tolerance and elimination. Because steadystate gut mucosal immunity relies on a fluctuating equilibrium, the disruption of intestinal homeostasis can lead to chronic remittent or progressive inflammatory disorders, especially inflammatory bowel diseases (IBDs) including Crohn’s disease and ulcerative colitis, and disruption of the intestinal mucosa [1]. Genetic polymorphisms associated with the host gut immune system and epithelial barrier predispose to the onset of IBDs [2]. These include components involved in the innate and adaptive immune responses, maintenance of intestinal epithelial barrier function including autophagy, endoplasmic reticulum stress response, mucus secretion, www.co-rheumatology.com

and antimicrobial activity pathways that determine tolerance, train immune cells, and maintain the balance between T helper 17 (Th17) cells with effector function and regulatory T (Treg) cells with inhibitory task [2,3]. For example, X-box binding protein 1 (Xbp-1) is a transcription factor whose functional impairment in intestinal epithelial cells (IECs) is implicated in the loss of Paneth and goblet cells, the initiation of intestinal inflammation, and the development of IBDs [4]. Another Crohn’s disease risk allele, autophagy-related 16-like 1 a International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, bMedical Mycology Research Center, Chiba University, Chiba and cDivision of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Correspondence to Hiroshi Kiyono, DDS, PhD, Division of Mucosal Immunology, Department of Microbiology and Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel: +81 3 5449 5270; fax: +81 3 5449 5411; e-mail: [email protected] Curr Opin Rheumatol 2015, 27:388–396 DOI:10.1097/BOR.0000000000000192 Volume 27  Number 4  July 2015

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The gut microbiota and inflammatory bowel disease Goto et al.

KEY POINTS  Mutual relationship between gut microbiota, intestinal epithelial cells, and intestinal immune cells provides a homeostatic environment in the intestine.  Dysbiosis of gut microbiota, aberrant function of the intestinal epithelial barrier and innate and acquired immune system predispose to the development of IBDs.  Control of commensal bacteria is a useful tool and attractive strategy of clinical application for IBDs.

(Atg16L1) that relates to autophagosome formation and degradation of long-lived proteins, also regulate function of Paneth cells and intestinal homeostasis [5,6]. In fact, granule formation and exocytosis of Paneth cells are severely impaired in mice lacking Atg16L1 and Crohn’s disease patients homozygous for the Atg16L1 [5,6]. However, IBD-associated alleles are present in healthy individuals as well,

thus suggesting the complexity of the etiologic mechanisms of IBDs. In addition to IBD-predisposing genetic features, various environmental factors, especially commensal bacteria, are now known to be key triggers for the onset of IBDs [7]. Commensal bacteria have a crucial role in calibrating the intestinal immune response and epithelial barrier system. For example, segmented filamentous bacteria (SFB) and Clostridia, two defined residents of the intestinal microbiota, drive the differentiation of Th17 and Treg cells, respectively, thus coordinating the effector and inhibitory arms of the gut immune system and achieving intestinal homeostasis [8–11]. Conversely, environmental factors such as infection and antibiotic treatment that disrupt the dynamics of the healthy microbiota (that is, dysbiosis) can initiate the pathologic inflammatory cascade leading to IBDs (Fig. 1). In this review, we summarize the influences of the gut immune response, epithelial barrier system, and intestinal microbiota on IBDs

Extrinsic factors

Intrinsic factors

(environment)

(genetic background)

Epithelial barrier breach Apoptosis Antimicrobial peptide Epithelial fucose Infection (toxin)

e.g., Salmonella Shigella Cholera EPEC

Aberrant negative immune response Suppressive cytokine (e.g. IL-10, TGFβ)

IBD

Dysbiosis (IBD-prone microbiota) Bacteroidetes Clostridia Enterobacteriaceae

Dysregulated immune response Inflammatory cytokines (e.g. TNF, IL-1β, IL-6)

FIGURE 1. Host (intrinsic) and environmental (extrinsic) factors interact to predispose the host to the development of inflammatory bowel diseases (IBDs). Intrinsic elements include genetic polymorphisms that affect epithelial barrier integrity and the positive and negative regulatory systems of intestinal immune cells. The intestinal immune system and epithelial barrier maintain the homeostasis of the gut microbiota and prevent the infection of pathogens. Extrinsic elements, especially those derived from commensal and pathogenic bacteria, both contribute to IBDs and modulate the intestinal immune system. Therefore, intrinsic and extrinsic sources interact to generate both physiologic and pathologic conditions of the digestive tract. 1040-8711 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

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and present potential opportunities for the translation of this knowledge into clinical therapies.

EPITHELIAL BARRIER SYSTEM AND COMMENSAL BACTERIA In addition to their immunologic role in the gut immune system, IECs constitute a physical and chemical barrier against external antigens, including commensal bacteria [12]. Underscoring the importance of IECs in the maintenance of intestinal homeostasis is the evidence that dysfunction of nuclear factor-kB (NFkB) signaling molecules such as IkappaB kinase IKKg (NF-kB essential modulator; NEMO) and transforming growth factor-b-activated kinase 1 (TAK1) leads to IEC death and spontaneous intestinal inflammation [13,14] (Fig. 2a). Breach of the epithelial barrier in mice lacking IEC-specific NEMO allows the translocation of commensal bacteria, leading to the detrimental production of inflammatory cytokines such as tumor necrosis factor (TNF) from mucosal myeloid-lineage cells and enhancing epithelial apoptosis [14]. Although commensal bacteria

generally are considered nonpathogenic, they can thus become opportunistic pathogens when the mucosal barrier system is disrupted and then induce local and systemic inflammation. In contrast to their role as triggers of inflammatory disorders, commensal bacteria and their metabolites promote the barrier function of the intestinal epithelium. For example, Bifidobacterium longum generates acetate, which inhibits the Shiga toxin produced by Escherichia coli O157:H7 from causing intestinal epithelial apoptosis [15]. Epithelial apoptosis allows the consequent opportunistic infection by commensal bacteria and induction of inflammatory cytokines [14]. Therefore, the inhibition of epithelial apoptosis by metabolites from commensals contributes to the homeostatic environment in the intestine. IECs are covered by thick mucus, which functions as a barrier against enteric microorganisms [16]. This mucus is secreted by goblet cells, has three major components (mucin glycoprotein, nonspecific microbicidal molecules, and immunoglobulin), and forms an outer and an inner layer [17].

(a)

(b)

TAK1

NEMO IKKα

TAK1/NEMO deficiency

MUC2 deficiency

TAK1

NEMO IKKα

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Apoptosis NFκB

NFκB

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(d)

α-defensin

Fut2 deficiency

NOD2 deficiency

Fut2

Fut2

NOD2

IL-22

IL-22 LT

LT ILC3

ILC3

FIGURE 2. The epithelial barrier system for maintaining gut homeostasis. (a) Epithelial intrinsic prosurvival NFkB signaling, including transforming growth factor-b-activated kinase 1 (TAK1) and NF-k B essential modulator (NEMO), contributes to the maintenance of the epithelial barrier system. Disruption of this NFkB signal leads to apoptosis and epithelial breach. (b) Muc2 regulates mucus secretion from goblet cells. Ablation of mucus secretion allows commensal bacteria access into epithelial cells, resulting in the development of intestinal inflammation. (c) The bacterial recognition receptor nucleotide-binding oligomerization domain (NOD) 2 regulates a-defensin expression in Paneth cells. NOD2 is an important gene in Crohn’s disease. (d) Fut2, another gene associated with Crohn’s disease, regulates epithelial fucosylation. Commensal bacteria, including segmented filamentous bacteria (SFB), and IL-22 and lymphotoxin (LT) produced from type 3 innate lymphoid cells (ILC3) induce the epithelial expression of Fut2. Inactivation of Fut2 leads to dysbiosis of gut microbiota. 390

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Although the outer layer is larger in volume, due to proteolytic cleavage of mucin, the two layers are similar in their protein composition and constituted by the gel-forming mucin MUC2 [17]. The inner mucus layer is densely packed and firmly attached to the epithelium, thus restricting commensal bacteria to the outer layer and preventing their direct interaction with the epithelium [17]. However, in mice that lack MUC2, the inner mucus layer is defective, thereby leading to direct contact between commensals and epithelium and to the development of colitis and spontaneous colonic cancer [18,19] (Fig. 2b). In addition to mucus, IECs express various glycoproteins on their surface, including membrane-bound MUC1. MUC1 functions as a physiologic barrier against luminal antigens and prevents excessive Th17 responses during inflammation [20]. MUC1 has been reported to be one of the susceptible genes of Crohn’s disease [2]. The subset of IECs known as Paneth cells is located in the crypt region of villi; these cells produce antimicrobial molecules such as a-defensin and RegIIIg to keep the crypt region free from colonization by commensal bacteria [21,22]. In this way, the bactericidal molecules from Paneth cells spatially segregate pathogenic and commensal bacteria and prevent them from penetrating the intestinal mucosa [22,23]. Several antimicrobial molecules including secretory phospholipase A2, lysozyme, and various members of the b-defensin family are expressed independently of the gut microbiota [24–26], whereas stimulation by enteric bacteria induces the production of a-defensin, C-reactive protein-ductin, resistin-like molecule b, RegIIIb, and RegIIIg [22,27–29]. In particular, the expression of a-defensin is regulated by nucleotide-binding oligomerization domain (NOD) 2, which recognizes muramyl-dipeptide bacterial components [27] (Fig. 2c). This finding is noteworthy because homozygous mutation of NOD2 is implicated in the development of Crohn’s disease [30]. In addition to endogenous IEC systems, mucosal immune cells regulate the expression of commensalinduced antimicrobial molecules. For example, the expression of RegIIIg by IECs is regulated by interleukin 22 (IL-22) derived from type 3 innate lymphoid cells (ILC3s) and Th17 cells, respectively, representing innate and acquired arms of host immunity, and by the endogenous MyD88-dependent epithelial bacterial recognition system [22,28]. In addition, IL-22R is expressed specifically on the basement membrane of IECs; therefore, IL-22 from ILC3 and Th17 cells directly activates IECs to induce the gene expression of factors such as RegIIIg. Another Crohn’s disease-related gene that may affect epithelial barrier system is that encoding

fucosyl transferase 2 (Fut2). Fut2 adds terminal a1, 2-fucose residues on carbohydrate chains expressed on IECs [2,3]. Epithelial fucose has been reported to promote the symbiosis between the host and commensal bacteria, because Bacteroides fragilis and B. thetaiotaomicron can forage epithelial fucose for use in extracellular components, in the expression of genes encoding enzymes in fucose metabolism such as FucI, FucA, and FucK, and as an energy source [31,32]. In addition, several pathogenic microorganisms including Norwalk virus, rotavirus, Salmonella typhimurium, and Helicobacter pylori attach to epithelial fucose, such that epithelial fucosylation is an interface of reciprocal interaction between the host and enteric microorganisms [33–35]. These findings allow us to speculate on the role of epithelial fucosylation in the regulation of homeostasis of gut microbiota and pathogenic microorganisms. In fact, humans who are homozygous for a Fut2 nonsense polymorphism and mice that lack Fut2 have aberrant microbiota [36,37] (Fig. 2d). Furthermore, mice lacking Fut2 are susceptible to the inflammation induced by infection with pathogenic bacteria such as Citrobacter rodentium and Salmonella typhimurium [38 ,39]. Given that the Fut2 nonsense polymorphism is associated with mucosal and systemic inflammatory disorders such as type I diabetes and primary sclerosing cholangitis as well as Crohn’s disease [2,40,41], the dysbios is caused by defects in epithelial fucosylation may create an inflammationprone gut microbiota. Although the mechanism of Fut2 expression in IECs is not fully understood, several recent reports including one from our group indicate that commensal and pathogenic bacteria cooperate with mucosal immune cells, especially ILC3 s, in the regulation of epithelial Fut2 expression [38 ,39,42]. In this scenario, commensal and pathogenic bacteria stimulate ILC3 s to produce IL-22, which signals through IL-22R on IECs to induce the expression of Fut2 and subsequent fucosylation of IECs (Fig. 2d). Together, these findings show that the epithelial barrier system, including mucus secretion, the production of bactericidal molecules, and glycosylation, is crucial to maintaining intestinal homeostasis and preventing deleterious inflammation. &&

&&

MUTUAL RELATIONSHIPS BETWEEN COMMENSAL BACTERIA AND GUT IMMUNE CELLS As described earlier, the epithelial barrier system typically constrains commensal and pathogenic bacteria within the intestinal lumen. Even so,

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commensal bacteria remain able to physiologically regulate mucosal immune cells under homeostatic conditions. For example, SFB drive the differentiation of Th17 cells and Immunoglobulin A (IgA)þ B cells and the proliferation of intraepithelial lymphocytes [10,11,43]. Th17 cells induced by SFB reportedly facilitate the development of autoimmune arthritis and experimental autoimmune encephalomyelitis [44,45]. In addition, intestinal dendritic cells have recently been found to present SFB antigens to naive T cells through an MHCIIdependent mechanism, leading to the differentiation of Th17 cells [46 ,47 ]. It currently remains unclear how dendritic cells take up SFB antigens from the intestinal lumen. Perhaps a subset of dendritic cells extends dendrites into the lumen to acquire bacterial antigens; villous M cells may be an alternative route for the uptake of SFB antigens [48]. Furthermore, classic M cells, located in the follicle-associated epithelium of Peyer’s patches, take up bacterial antigens, transfer them to resident dendritic cells, and thus initiate antigen-specific immune responses [49]. Because SFB occur in the epithelial layers of both intestinal villi and Peyer’s patche, additional investigation is needed to clarify wherein these SFB-induced pathogenic Th17 cells are induced [e.g. in organized lymphoid tissues (such as Peyer’s patches) or the diffuse lamina propria region] and how they migrate to the pathologic sites of autoimmune diseases. SFB-induced Th17 cells have a specific T-cell receptor and proliferate in response to SFB antigens [46 ,47 ]. The mechanism through which this process contributes to the development of systemic autoimmune diseases presents another frontier for future investigation. One possibility is that Th17 cells induced by SFB crossreact with autoantigens; SFBderived Th17 cells may migrate to induce local cytokine production and accelerate systemic inflammation [50]. These lines of inquiry will clarify how the gut microbiota influences the development of systemic autoimmune diseases. In addition to presenting antigen, lamina propria dendritic cells produce inflammatory cytokines, including IL-23 that subsequently stimulate Th17 cells and ILCs [51]. For example, bacterial flagellin stimulates intestinal lamina propria TLR5þ dendritic cells to produce IL-23 [51]; this cytokine then induces Th17 cells and ILC3s to express IL-22, which stimulates IECs to produce RegIIIg [11,52]. In the context of the development of IBDs, the IL-23– Th17–ILC3 axis is notable because several of its components, including IL12p40, IL23R, C-C chemokine receptor 6, Janus kinase 2, signal transducer and activator of transcription 3, lymphotoxin a, and lymphotoxin b, are Crohn’s disease-associated &

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genes [2]. Except for lymphotoxin, which is produced by ILC3s only, most of the genes of the IL-23– Th17–ILC3 axis are expressed by both Th17 cells and ILC3 s and characterize the differentiation and function of these cells. Indeed, both Th17 cells and ILC3 s representing acquired and innate immunological arms, respectively, have been reported to have critical roles in the induction of IBDs [53,54]. As described earlier, IL-22 promotes the fucosylation of IECs and their expression of antimicrobial molecules; these factors subsequently prevent the invasion of pathogenic bacteria and regulate the gut microbiota for its harmonized participation in host mucosal immunity [23,28,38 ,39]. In addition to preventing the entrance of luminal bacteria, IL-22 from ILC3 s blocks the dissemination of intratissue commensal Alcaligenes from the Peyer’s patches into systemic compartments and inhibits subsequent systemic inflammation [55,56]. Although the mechanism through which IL-22 prevents bacterial dissemination remains unclear, antimicrobial molecules induced by IL-22 presumably help to contain Alcaligenes organisms within Peyer’s patches, a key inductive site for the mucosal immune system [56]. Together these findings indicate that the combined IL-23–Th17–ILC3–IL-22 axis harmonizes the microbiota with the epithelial barrier system to achieve gut homeostasis. Some commensal bacteria, including Enterococcus gallinarum, E. mundtii, and E. faecalis, release ATP during their exponential growth phases [57]. This bacteria-derived extracellular ATP promotes host– microbial mutualism in the intestinal compartment by regulating development of follicular helper T (Tfh) cells and inducing Th17 cells [58,59 ] (Fig. 3a). Tfh cells express both C-X-C chemokine receptor type 5 (CXCR5), programmed cell death 1, and CD4, and they interact with B cells in germinal centers [60]. Tfh cells help B cells to generate highaffinity antibody-producing plasma cells via the production of IL-21 from Tfh cells [60]. Tfh cells in Peyer’s patches express highest levels of P2X7 within the immune cells in Peyer’s patches, one of the receptors for extracellular ATP [59 ]. The extracellular ATP–P2X7 pathway is involved in cell life cycle: mice lacking P2X7 showed an expansion of Tfh cells in Peyer’s patches, which upregulated the production of high-affinity Immunoglobulin A (IgA) against commensal bacteria [59 ] (Fig. 3a). In fact, P2X7-deficient mice have increased numbers of neutralizing IgA-coated commensal bacteria, and SFB counts at luminal sites are diminished [59 ] (Fig. 3a). In addition to the observed decrease in numbers of commensal bacteria, steady-state serum levels of bacterial components, such as LPS, also appeared to be decreased in P2X7-deficient mice. &&

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Homeostasis

(a)

Inflammation

(b)

Tissue damage

Commensal mutualism SFB Bacteriaderived ATP

Bacteria-derived ATP

P2X7 Homeostatic reduction of Tfh

IgA

P2R

Induction of inflammatory DC

Tfh Induction of

Extracellular ATP (danger signal)

P2X7

Th17

IgA+ plasma cell induction

High-affinity IgA

Mast cell Th17

Migration Lamina propria

Peyer’s patches

Inflammatory responses

FIGURE 3. Commensal mutualism and inflammatory responses regulated by extracellular ATP-P2X7 receptor pathways. (a) Commensal bacteria-derived ATP stimulates P2X7 on Tfh cells and modulates their numbers. Once this pathway is disrupted, expansion of Tfh cells is induced, which results in high-affinity IgA production against commensal bacteria. Highaffinity IgA acts as a neutralizing antibody against commensal bacteria and diminishes the bacteria (e.g. segmented filamentous bacteria, SFB) at the luminal sits. (b) Extracellular ATP is released upon stimulation of immune cells and causes cellular damage. Extracellular ATP induces activation of mast cells as well as induction of T helper 17 (Th17) cells via generation of inflammatory-type dendritic cells.

Accordingly, P2X7-deficient mice have reduced levels of serum Immunoglobulin M (IgM) against blood-borne infectious microbes [59 ]. These findings suggest the critical role of the ATP–P2X7 axis for the Tfh cell-mediated IgA production in order to create the appropriate interface between the host and commensal microbiota. In addition to regulating Tfh cells, commensalderived extracellular ATP induces intestinal Th17 cells, which promote intestinal inflammation [58]. Increases in commensal-derived ATP due to a deficiency of ATP-hydrolyzing enzymes promote the generation of Th17 cells in the intestinal compartment [58]. Several pathways for the ATP-driven generation of Th17 cells have been suggested. For example, ATP-stimulated IECs produce IL-6, Transforming growth factor (TGF)-b, and thymic stromal lymphopoietin; these cytokines induce inflammatory-type dendritic cells to produce various cytokines (e.g. IL-6, IL-23, and TGF-b) to promote the generation of Th17 cells [61] (Fig. 3b). In contrast to the indirect pathway, ATP might directly stimulate CD4þ T cells as costimulatory agents and increase the differentiation of Th17 cells [62]. Several studies [63–65] from our lab and others have indicated that extracellular ATP, released from damaged and activated cells (e.g. mast cells and macrophages), acts as a ‘danger signal’ that initiates intestinal inflammation by binding P2X7 receptors. &

For example, P2X7 levels are increased in the intestinal tissues of patients with Crohn’s disease [63,65]. In addition, P2X7 signaling induces the production of inflammatory cytokines (e.g. TNFa and IL-1b), chemokines (e.g. CXCL1, 2, and CCL2), and lipid mediators (e.g. leukotrienes B4 and C4) from mast cells [63]. Therefore, the lack or inhibition of P2X7 on intestinal mast cells reduced intestinal inflammation [63] (Fig. 3b). Recent studies revealed that limiting P2X7 signaling on mast cells via inhibitory receptors, such as CD300f, resulted in the suppression of intestinal inflammation [66]. These results reveal that extracellular ATP from commensal bacteria and host sources plays important role in both homeostasis and inflammation in the intestine.

RECENT PROGRESS IN THE CLINICAL APPLICATION OF THE COMMENSAL MICROBIOTA TO THE CONTROL OF INFLAMMATORY BOWEL DISEASES To combat inflammatory intestinal disorders, some of the current pharmacologic approaches (e.g. therapeutic antibodies) have targeted various cytokines involved in the immune response, including TNF-a, IL-1, IL-6, IL-12, and IL-23 [67]. In addition, because of the role of dysbiosis in causing intestinal inflammation [68], modulating or renewing gut microbial populations has emerged as an attractive alternative

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for controling gut immunity [68]. Various microbially based strategies for treating IBDs, including probiotics, prebiotics, and antibiotics, have recently emerged as beneficial options for patients with intractable disease [69,70]. In particular, species belonging to Lactobacillus, Bifidobacterium, and Streptococcus are clinically beneficial for the downregulation of intestinal inflammation [69,70]. For example, patients with ulcerative colitis improved clinically after treatment with VSL#3, a mixture comprising live bacteria from three strains of Bifidobacterium (B. longum, B. breve, and B. infantis), Streptococcussalivarius subs p. thermophilus, and four strains of Lactobacillus(L. casei,L. plantarum, L. acidophilus, and L. delbrueckiisubsp.bulgaricus) [70]. Lactobacillus strains promote an antiinflammatory milieu through several of their cell wall components (e.g. peptidoglycan, PGN) [71,72]. The PGN from Lactobacillus strains reduces intestinal inflammation by inducing regulatory dendritic cells, which produce molecules that promote the generation of Treg cells [72], such as IL-10, TGF-b, and indoleamine 2, 3-dioxygenase [71,72]. In addition, Lactobacillus strains produce proteases, such as lactoceptin, to ameliorate intestinal inflammation [73]. The lactoceptin produced by Lactobacillus casei selectively degrades several cell migration-related chemokines, including CXCL9, CXCL10, CXCL11, and CXCL12, thus inhibiting the infiltration of lymphocytes into the inflammatory compartment [74]. Indeed, CXCL10, which induces the recruitment of activated pathologic T cells via its receptor, CXCR3, is highly produced in patients with ulcerative colitis, and therefore is a potential therapeutic target for that disease; CXCL10’s-blocking antibody, MDX1100, has entered the clinical trial process [75]. In addition, Bifidobacterium species, such as Bifidobacterium breve, have the potential to stimulate CD103þ dendritic cells in the gut [70], leading to the production of IL-10 and IL-27 via the TLR2–MyD88 pathway and the generation of Tr1 cells, a suppressor T-cell family [76]. Indeed, the administration of B. breve ameliorated colitis in a murine model [76]. Recent evidence has indicated that the numbers of Clostridium organisms (clusters XIV, XVIII, IV) are reduced in IBD patients; the administration of these Clostridium species induced the production of Treg cells, inhibited intestinal inflammation, and decreased allergic symptoms [8,9]. Prebiotics provide metabolic fuel (e.g. oligosaccharides) for the support and proliferation of beneficial commensal bacteria [70,77]. For example, providing fructo-oligosaccharides or lactulose increased the numbers of beneficial commensal bacteria, especially Lactobacillus and Bifidobacterium species, and clinically prolonged remission in IBD 394

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patients [78,79]. Other important microbial metabolites include short-chain fatty acids (acetate, propionate, and butyrate), and organic fatty acids generated through the bacterial fermentation of polysaccharide and oligosaccharide-containing proteins in the colon [80]. Short-chain fatty acids derived from soluble dietary fiber reportedly mediate the differentiation of naive T cells into Treg cells [81]. As another example, butyrate enhances histone H3 acetylation in the promoter and conserved noncoding sequence regions of the Foxp3 locus; this process might explain the mechanism underlying how Clostridium, a prominent class of commensal microbes, induces colonic Treg cells [80]. In addition, colony counts of butyrate-producing species, such as Roseburia hominis and Faecalibacterium prausnitzii are decreased in patients with ulcerative colitis [82]. Fecal microbiota transplantation (FMT) offers a possibility as a well tolerated, effective, inexpensive, and rapid method for successfully decreasing intestinal inflammation [69]. In FMT, feces from a healthy donor are transferred into the intestinal tract of a patient with intestinal inflammation. In doing so, a healthy intestinal microbial community is restored in the patient. For example, it has become common practice to cure Clostridium difficile infection by using FMT [83]. As reported, the gut microbiota is involved in many diseases that occur far from the intestinal compartment, including arthritis, systemic lupus erythematosis, asthma, type 2 diabetes, neuronal disorders, and obesity [83,84]. Even behavior and emotions are affected by the microbiota [85]. These extraintestinal disorders are potential targets for FMT. Indeed, FMT has recently shown beneficial effects in cases of multiple sclerosis and Parkinson’s disease [84]. Accordingly, the manipulation of the intestinal microbiota may represent an alternative strategy for curing not only intestinal disorders but also extraintestinal diseases. It should be noted that additional and continuous clinical research and trial are necessary for the use of FMT in daily clinical practice.

CONCLUSION We now recognize that intestinal commensal bacteria affect our health. Accumulating evidence has gradually revealed the molecular basis of the symbiosis and intratissue cohabitation between host immunity and the commensal bacteria that reside at mucosal body surfaces. In particular, components of the innate and acquired immune systems are regulated by commensal bacteria and their metabolites. For example, a mixture of 17 strains within clusters IV, XIVa, and XVIII of Clostridium was Volume 27  Number 4  July 2015

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needed to induce colonic Treg cells [8]. Together these findings show that we need to understand not only the symbiotic association between the host and commensal bacteria but also the cooperative relationship between bacteria and their metabolites. Future efforts to decipher the underlying mechanisms of IBDs likely will reveal new strategies to control and cure intestinal inflammation through targeting abnormal bacterial communities. Acknowledgements We appreciate our former and current colleagues and collaborators who have been providing their expertise for our understanding of cross-communication between the gut immune system and commensal microbiota. Financial support and sponsorship This work was supported by grants from the Core Research for Evolutional Science and Technology Programme of the Japan Science and Technology Agency (to H.K.), the Ministry of Education, Science, Sports, and Technology of Japan [MEXT: Grant-in Aid for Scientific Research S (H.K.) and Research Activity Start-up (26893047 to Y.K)]., the Young Researcher Overseas Visits Programme for Vitalizing Brain Circulation (Japan Society for the Promotion of Science, H.K.) and MEXT Translational Research Network Programme (at the University of Tokyo) Seeds B and C. Conflicts of interest There are no conflicts of interest.

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Volume 27  Number 4  July 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

The gut microbiota and inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) reflect the cooperative influence of numerous host and environmental factors, including those of elements of the in...
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